Vascular proliferative disorders are conditions within the walls of blood vessels, including arteries and veins, which result in occlusion or blockage of blood flow. A common vascular proliferative disorder is restenosis. Restenosis is a major clinical problem associated with coronary angioplasty. Restenosis generally occurs within about 0 to 6 months in about 30% to 50% of patients who undergo balloon angioplasty to clear clogged coronary arteries in an effort to prevent and treat heart disease due to occluded arteries. The resulting restenosis causes substantial patient morbidity and health care expenses.
The process of restenosis is initiated by injury of the vessel, with the subsequent release of thrombogenic, vasoactive, and mitogenic factors. Endothelial and deep-vessel injury leads to platelet aggregation, thrombus formation, inflammation, and activation of macrophages and smooth-muscle cells. These events induce the production and release of growth factors and cytokines, which in turn may promote their own synthesis and release from target cells. Thus, a self-perpetuating process is initiated.
There currently are no effective treatments available for restenosis. Accordingly, a major medical need exists for effective treatments for restenosis and other vascular proliferative disorders.
We have now discovered that certain polyamines are effective for inhibiting vascular smooth muscle proliferation, and as such are useful in treating and preventing vascular proliferative disorders such as restenosis. There are numerous polyamines known in the art. Many are under active investigation as potential treatments for neoplastic and viral diseases. For example, EP 0349,224 describes a series of polyamines related to spermine, spermidine, norspermidine, homospermidine, and putrescine (1,4-diaminobutane). The compounds are said to be anti-neoplastics, antivirals, anti-retrovirals, and anti-psoriasis agents. Similarly, EP 0277,635 describes the synthesis of certain polyamines which are said to be useful for treating diseases caused by infestation with a variety of parasitic protozoa. EP 0399,519 describes the use of certain polyamines to potentiate cell-mediated immunity. EP 0162,413 discloses polyamines for use in treating neoplasms. U.S. Pat. No. 4,507,321 describes the use of polyamines to stimulate epithelial cell regrowth for wound healing. Japanese Patent No. 85/6348 describes several new polyamines for use in cell proliferation.
Endean, et al., in J. Surgical Research, 50:634-637 (1991) discloses that polyamines which exist in biological systems are synthesized from ornithine through the action of ornithine decarboxylase. The authors describe experiments to block the activity of this enzyme, thereby reducing polyamine synthesis, thus inhibiting the formation of intimal hyperplasia, which is said to be a significant cause of restenosis. It has also been demonstrated that certain polyamine analogs, including the compounds described in this application, are effective agents for inducing the transcription of spermine-spermidine acyltransferase, or SSAT. SSAT is an important enzyme in the regulation of pool sizes of polyamines, and induction of this enzyme increases the rate at which polyamines are metabolized and removed from the cell, thereby depleting their levels. This is an effective method for inhibiting proliferation of, for example, cancer cells, as taught by Fogel-Petrovic M; Shappell NW; Bergeron, R. J.; Porter, C. W., J. Biol. Chem. 7(8):653-61 (1993).
An object of this invention is to provide a method for treating and preventing proliferative vascular disorders, such as restenosis associated with angioplasty.